(a) Field of the Invention
This invention relates to hexahydroindolizinones, which are useful as inhibitors of cardiac arrhythmias and of platelet aggregation and are therefore useful in the treatment of irregular heartbeat and in the prevention of thrombus formation.
Arrhythmias are disorders relating to electrical impulse generation in the heart. The disorders include premature contractions (extrasystoles) originating in abnormal or ectopic foci in atria or ventricles; atrial flutter; atrial fibrillation; and ventricular tachycardia and fibrillation. For a discussion on these disorders, see, for example, L. S. Goodman and A. Gilman, eds., The Pharmacological Basis of Therapeutics (New York, 1980), Sixth Edition, pp. 761-767.
A number of compounds have been developed to alter cardiovascular function related to heart rate and rhythm. The cardiac glycosides, including digitalis, have as their main pharmacodynamic property the ability to increase the force of myocardial contraction. This positive inotropic action is the basis of the salutory effects of these cardiac glycosides in congestive heart failure--increased cardiac output; decreased heart size, venous pressure, and blood volume; and diuresis and relief of edema. See, e.g., Goodman and Gilman at pp. 730-731, 750-751. Quinidine is useful in the therapy of atrial fibrillation but exhibits several toxic reactions, such as cinchonism. Goodman and Gilman at pp. 768-774. Procainamide acts in essentially the same manner as quinidine, and also exhibits toxic side effects. Goodman and Gilman at pp. 774-777. Lidocaine, a widely used local anesthetic, may be used in the treatment of ventricular arrhythmias, but must be administered by injection. Goodman and Gilman at pp. 779-781. Propranolol is useful in the treatment of supraventricular tachycardias and ventricular arrhythmias, but must be used with great care because it may induce significant hypotension, left ventricular failure, or even cardiovascular collapse. Goodman and Gilman at pp. 783-786. Disopyramide has effects somewhat like procainamide and quinidine, all being so-called Type 1 antiarrhythmics. At therapeutic levels disopyramide shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the refractory period of the A-V node. Goodman and Gilman at pp. 777-779. However, because of the anticholinergic effects of some of the Type 1 antiarrhythmics, such as disopyramide, they should not be used in patients with glaucoma, myasthenia gravis, or problems of urinary retention.
Although part of an important defense mechanism in traumatic injury, thrombus formation can also lead to harmful ischemic or occlusive incidents. Platelet aggregation plays an important part in such thrombus formation. Antithrombotic drugs that reduce the reactivity of circulating hypersensitive platelets may be useful in the prevention and treatment of thrombotic disorders and are particularly advantageous in the prevention of coronary thrombosis associated with myocardial infarction. See, e.g., Goodman and Gilman at pp. 1360-1361. The antiarrhythmic activity of the compounds of the present invention is likewise important in the management of arrhythmias resulting from myocardial infarcts.
(b) Prior Art
As previously described, a number of compounds are useful in the treatment of cardiac arrhythmia. U.S. Application Ser. Nos. 06/532120 filed Sept. 14, 1983 and 06/635,989 filed July 30, 1984 disclose certain antiarrhythmic 1,3-diazabicyclo[4.4.0]decan-4-ones and 1,3-diazabicyclo[4.4.0]dec-2-en-4-ones, each of which has a decalin-like skeleton (i.e., two fused six-membered rings) containing two ring nitrogen atoms, one of which is at a bridgehead position. In contrast, the compounds of the present invention are hexahydroindolizinones (or 1-azabicyclo[4.3.0]nonan-9-ones), each of which has a bicyclic skeleton of fused five- and six-membered rings containing a single ring nitrogen at a bridgehead position. The compounds of Ser. No. '120 and of this invention are further distinguished by the distinctly different locations of substituents around the rings.